Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy

By Min H Kang, P. Reynolds. Clinical Cancer Research, 2009

1,028 citations recorded by the source corpus.

Defects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic pathway. It is controversial whether some BH3-domain proteins (Bim or tBid) directly activate multidomain pro-apoptotic proteins (e.g., Bax and Bak) or act via inhibition of those anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that stabilize pro-apoptotic proteins. Overexpression of anti-apoptotic Bcl-2 family members has been associated with chemotherapy resistance in various human cancers, and preclinical studies have shown that agents targeting anti-apoptotic Bcl-2 family members have preclinical activity as single agents and in combination with other antineoplastic agents. Clinical trials of several investigational drugs targeting the Bcl-2 family (oblimersen sodium, AT-101, ABT-263, GX15-070) are ongoing. Here, we review the role of the Bcl-2 family in apoptotic pathways and those agents that are known and/or designed to inhibit the anti-apoptotic Bcl-2 family of proteins.

Subfields: Molecular Biology, Organic Chemistry

View Paper: https://www.semanticscholar.org/paper/811f915bb24f549e6adeac1707166d00f7c81717

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Citations in the corpus

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors (2016, neutral): “1 (Kang & Reynolds, 2009; Vogler et al., 2009; Strasser et al., 2011; Czabotar et al., 2014; Correia et al., 2015)).”
The BCL-2 Family Reunion (2010, background): “One example is Genasense, a phosphorothioate oligodeoxynucleotide bcl-2 antisense, which has been shown to sensitize CLL patients to chemotherapy (Kang and Reynolds, 2009) and phase III trials suggest that Genasense may have efficiency in advanced melanoma with combination therapies (Bedikian et…”
From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors (2017, background): “Furthermore, in vivo assessments of singleagent venetoclax in human xeno graft models of B cell lymphoma with the t(14;18) trans location and models of ALL showed dosedependent tumour inhibition and growth delay43.”
Autophagy in malignant transformation and cancer progression (2015, positive): “These proteins are overexpressed by a wide variety of hematological and solid tumors, an event that consistently reduces the sensitivity of neoplastic cells to lethal cues of either cell-intrinsic or environmental origin (Kang & Reynolds, 2009; Anderson et al , 2014).”
Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies (2016, background): “The activities of IAPs, however, may be suppressed by mitochondrial proteins, such as Omi/HtrA2 and Smac/DIABLO, released into the cytosol during apoptosis (Figure 4).”